Alleviation of Sleep Apnea in Patients with Chronic Renal Failure by Nocturnal Cycler–Assisted Peritoneal Dialysis Compared with Conventional Continuous Ambulatory Peritoneal Dialysis

Part 1: Comparative Study in Prevalent Patients

Between September 2001 and January 2004, we performed overnight PSG in 23 of 26 prevalent NPD patients who were followed at our center. These patients were not assessed for the presence of sleep apnea before enrollment. The remaining three patients declined to participate in the study. Because of the inherent complexity in establishing a patient on a particular system of NPD or CAPD, we initially believed that it was not feasible to perform crossover comparison by recording PSG on the same patient while he or she was on maintenance NPD or CAPD. To circumvent this problem, we performed overnight PSG in stable CAPD patients who were matched for demographics, body mass index (BMI), comorbidities, adequacy of dialysis, and peritoneal transport properties, chosen from the existing pool of 392 prevalent CAPD patients who were followed at our center. The selection of control subjects was based purely on these clinical parameters without regard to other personal attributes or symptoms that pertained to sleep disturbances. Twenty-three patients agreed to undergo PSG. All patients had to have been deemed clinically euvolemic with serum sodium between 135 and 145 mmol/L upon study entry, and there could not have been any peritonitis episode within a 3-mo period before PSG.

Part 2: Fixed-Sequence Intervention Study in Incident Patients

From January 2004 through April 2006, we performed a modified crossover study, which effectively was a fixed-sequence intervention, to validate our hypothesis in the comparative study described in part 1. We made use of the fact that in Hong Kong all incident patients who required CAPD had to undergo, after Tenckhoff catheter placement, a temporary period of mandatory cycler-assisted NPD for approximately 8 wk while awaiting their turn for CAPD training. Twenty-four consenting adult patients underwent one PSG study toward the end of their 6 to 8 wk of NPD treatment. They then underwent training for CAPD, and a second PSG study was performed as soon as they had been established on stable CAPD. All patients had to have been deemed clinically euvolemic with serum sodium between 135 and 145 mmol/L upon study entry and before PSG. The study protocol was reviewed and approved by the Institutional Review Board and Clinical Research Ethics Committee of each individual hospital, and all patients gave written informed consent to participate in the study.

Laboratory Measurements

Residual renal function was estimated by taking the average of urea and creatinine clearances calculated from 24-h urine samples and simultaneous serum urea and creatinine levels and corrected for body surface area. Complete blood count and standard renal function tests, including serum bicarbonate levels, were measured on the day of PSG. For NPD patients, the biochemical assays were performed just before and after PSG, and the values were averaged. For CAPD patients, measurements were obtained just before PSG. Adequacy of dialysis was assessed at the steady state using standard urea kinetic studies when patients were established on PD for approximately 2 mo. Peritoneal membrane transport properties were assessed at the same setting using a standard peritoneal equilibration test (6).

PSG

Comprehensive overnight PSG was performed in the hospital using an Alice 3 or Alice 4 machine (Healthdyne, Atlanta, GA). Recordings included electroencephalogram, electrooculogram, submental electromyogram (EMG), bilateral anterior tibial EMG, electrocardiogram, chest and abdominal wall movement (respiratory effort) by inductance plethysmography, airflow by a nasal pressure transducer (PTAF 2; Pro-Tech, Woodinville, WA), and finger pulse oximetry. All variables were recorded continuously by a computerized data-acquisition system and stored on an optical disk for subsequent analyses.

All polysomnograms were scored manually by an independent expert in sleep medicine without knowledge of the mode of dialysis, according to standard criteria (7). Apnea was defined as the cessation of airflow for >10 s, and hypopnea was defined as a reduction of airflow of ≥50% for >10 s plus an oxygen desaturation of ≥4%. An arousal was scored when there was an abrupt shift in electroencephalogram frequency to α or θ of ≥3 s or >16 Hz, after at least 10 s of sleep, or when during rapid eye movement sleep there was a concomitant rise in EMG tone (8). A respiratory arousal was defined as an arousal that occurred within 3 s after the termination of an episode of apnea or hypopnea. The average number of episodes of apnea and hypopnea per hour of sleep (apnea-hypopnea index [AHI]) was calculated as the summary measurement of sleep-disordered breathing.

Significant sleep apnea was defined arbitrarily as an AHI of ≥15 events per hour of sleep. An AHI >30 was classified as severe sleep apnea. Subjective sleepiness was evaluated by the Epworth sleepiness scale (ESS), a questionnaire that is specific to symptoms of daytime sleepiness, and the patients were asked to score the likelihood of falling asleep in eight different situations with various levels of stimulation, adding up to a total score of 0 to 24 (9). Patients with ESS >9 were considered to have excessive daytime sleepiness. Apneas were classified as central when there was no chest and abdominal movement, as obstructive when they moved paradoxically, and as mixed when an initial absence of ventilatory effort was followed by an obstructive apnea pattern upon resumption of effort. Cheyne-Stokes breathing (CSB) was defined as an episode of central apnea (or hypopnea) alternating with breathing that had a pattern of cyclical crescendo and decrescendo amplitude for at least 3 cycles of not less than 60 s each. Periodic leg movements were defined as four or more involuntary leg movements during sleep, each lasting 0.5 to 5.0 s, with 5 to 90 s between movements.

Dialysis Protocol

Upon initiation of dialysis, the particular PD system used was solely the choice of the patient after he or she had visited the PD center and received detailed information from the nurse specialist on the various brands, modes, and methods of connection of CAPD and NPD. In Hong Kong, all dialysis solutions are provided free by the statutory national health service. Patients only pay for consumable items, such as connection tubings and antiseptic solutions. Automated cyclers are provided free in most instances by the charitable Hong Kong Kidney Foundation. Therefore, patients who choose NPD rather than CAPD may have to bear a higher consumable expenditure in view of the larger number of connection tubings required. Otherwise, there is no selection bias between CAPD and NPD.

For NPD, patients performed overnight exchanges of 10 to 12 L of PD fluid at 2.0 to 2.2 L/cycle for five to six cycles using an automated cycler (HomeChoice; Baxter Healthcare, McGaw Park, IL). For CAPD, patients performed three to four daily exchanges of 2 L of PD fluid using UltraBag (Baxter Healthcare, Guangzhou, People’s Republic of China), StaySafe or AndyDisk (Fresenius Medical Care, Bad Homburg, Germany), or Gambrosol Trio (Gambro Lundia AB, Lund, Sweden) system. Dialysis regimens for both NPD and CAPD patients were adjusted to achieve euvolemia and a weekly KT/V_urea of 1.8 to 2.1. All patients who participated in the comparative study had to have been on stable maintenance PD for 12 mo or longer without concomitant or recent (within 3 mo) infective episode or hospitalization.

Bioelectrical Impedance Analysis

Bioelectrical impedance analysis (BIA) is a portable technique of assessing body water composition that has been cross-validated in PD patients (10,11). To assess changes in body water content as a result of NPD or CAPD, we performed BIA measurements using Nutrigard-M Bioelectrical Impedance Analyzer (Data Input GmbH, Darmstadt, Germany) while the patient was supine on a bed for at least 15 min on the night of PSG study before and the morning after NPD or the night dwell of CAPD with the peritoneum emptied. Multifrequency (5 to 100 kHz) currents were introduced at four distal electrodes placed on the dorsal surface of the nondominant hand and ipsilateral foot in a standard manner, and resistance (R) and reactance (Xc) were measured by proximal electrodes. The external calibration of the instrument was validated with a calibration circuit of known impedance value (R = 500 ohms, Xc = 144 ohms, error 0.8%). Total body water (TBW; in liters) was computed as described elsewhere (12) and as applied in PD patients (13): TBW for male patients = 1.203 + 0.449 H²/R + 0.176 W, and TBW for female patients = 3.747 + 0.45 H²/R + 0.113 W, where H is body height in cm, R is resistance at 100 kHz, and W is body weight in kg.

Extracellular water (ECW; in liters) was computed as described previously (14): ECW = 0.3 × H²/Z + 3.08, where Z is the impedance calculated according to the manufacturer’s instruction: Z = (R² + Xc²)^1/2 with R and Xc recorded at a frequency of 5 kHz. Intracellular water (ICW; in liters) was obtained by ICW = TBW − ECW.

Pulmonary Mechanics

Standard spirometry was performed in accordance with the guidelines of the American Thoracic Society (15) on the night of PSG before and the morning after NPD or the night dwell of CAPD. Flow-volume measurements yielded the following parameters: Forced vital capacity (FVC), forced expired volume in 1 s (FEV₁), peak expiratory flow rates at 50% (PEF_50%) and 75% (PEF_75%) of FVC, and peak inspiratory flow rate at 50% (PIF_50%) of FVC. Airflow limitation also was assessed using the peak flow ratios at mid-vital capacity (PIF/PEF_50%). Pulmonary function results were expressed as measured and predicted values. Predicted vital capacity, inspiratory and expiratory flow rates, and FEV₁ were based on gender, height, and age.

Statistical Analyses

Data were expressed as means ± SD unless otherwise specified. Statistical analyses were performed using SPSS for Windows software version 12.0 (SPSS, Inc., Chicago, IL). Comparisons between groups were performed by χ² test for categorical data and by Mann-Whitney U test for continuous data. Correlations between continuous variables were examined by linear regression analysis. Factors with P < 0.1 on univariate analysis were entered into a multivariate regression model with AHI as the dependent variable and age, BMI, dialysis vintage, serum albumin, peritoneal and residual Kt/V and creatinine clearance, peritoneal transport property (D/P of creatinine at 4 h), and the mode of PD as independent variables. A backward elimination procedure with P > 0.05 to remove was performed to identify independent factors of correlation. Nonparametric paired-sample Wilcoxon signed rank test was used to determine changes in sleep disturbance parameters in the fixed-sequence intervention group of patients. Comparison of within-group differences in prevalence of sleep apnea during NPD or CAPD was performed using the McNemar test. P < 0.05 was considered significant. All probabilities were two tailed.

Part 1

Baseline demographic and clinical parameters of the study patients were not different (Table 1). The underlying renal diseases in the NPD group were diabetes in nine, hypertensive nephrosclerosis in two, primary glomerulonephritis in four, neurogenic bladder in one, reflux nephropathy in one, and unknown in six. Those for the CAPD group were diabetes in 11, hypertensive nephrosclerosis in two, primary glomerulonephritis in two, lupus nephritis in one, reflux nephropathy in one, and unknown in six.

The prevalence of sleep apnea (AHI ≥ 15) was 52% for NPD patients and 91% for CAPD patients (P = 0.007). Such difference became insignificant when the AHI cutoff value was lowered to 10 or 5 (Table 2). The number of patients without significant sleep apnea (AHI < 15) was much higher in the NPD group, whereas the prevalence of severe sleep apnea (AHI > 30) was higher in the CAPD group (Figure 1), although the latter difference did not reach statistical significance. The overall sleep pattern is summarized in Table 3. The mean (±SD) AHI in NPD and CAPD patients was 31.6 ± 25.6 versus 50.9 ± 26.4 (P = 0.025), and the minimum oxygen saturation was 84.1 ± 8.4 versus 71.0 ± 17.7% (P = 0.008), respectively. The duration of the various stages of sleep, the frequency of arousals and periodic leg movements during sleep, and biochemical parameters were not significantly different between the two groups, although there was a trend toward more frequent arousals among CAPD patients.

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Figure 1.

Prevalence of sleep apnea by apnea-hypopnea index (AHI) in nocturnal peritoneal dialysis (NPD; □) and continuous ambulatory peritoneal dialysis (CAPD; ▪) patients.

The distribution of central, obstructive, and mixed types of hypopnea or apnea is shown in Figure 2. There was a trend that each type of sleep apnea was more frequently encountered in the CAPD group, although the difference from the NPD group did not reach statistical significance. Obstructive pattern was the most frequent type of apnea in both groups, followed by central and mixed types of apnea. CSB was observed in two NPD and three CAPD patients, all of whom had severe sleep apnea (mean ± SD AHI 35.3 ± 5.0; range 30 to 41.4). None of them had a history of cardiac failure or cerebrovascular disease, and echocardiogram estimated a left ventricular ejection fraction of 53.8 ± 4.4% (range 50 to 61%).

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Figure 2.

Pattern of sleep apnea in NPD (□) and CAPD (▪) patients.

Self-reported daytime sleepiness, as assessed by the ESS, was present in 10 (43%) NPD and eight (35%) CAPD patients. Multivariate regression analysis showed that only the mode of PD (r² = 0.351, b = 20.9; 95% confidence interval 3.9 to 38.0; P = 0.017) and BMI (r² = 0.386, b = 3.3; 95% confidence interval 0.8 to 5.8; P = 0.011) independently correlated with AHI.

Part 2

Twenty-four patients (13 men; mean age 50.8 ± 13.0 y; mean BMI 21.3 ± 3.5 kg/m²) participated in the fixed-sequence intervention study. Their underlying renal diseases were diabetes in five, IgA nephropathy in three, membranous nephropathy in one, lupus nephritis in one, focal segmental glomerulosclerosis in two, pauci-immune crescentic glomerulonephritis in two, polycystic kidney disease in one, and unknown in nine. The average interval between the two sets of PSG recordings was 5.03 ± 1.0 mo, and there was no appreciable change in residual renal function during this period (data not shown). Epworth daytime sleepiness was present in three (12.5%) patients during NPD and four (16.6%) patients during CAPD.

Using an AHI cutoff of 15, the prevalence of sleep apnea was 4.2% (n = 1) during NPD and 33.3% (n = 8) during CAPD (Table 4). When the AHI cutoff was lowered to 10, the prevalence was 12.5% (n = 3) during NPD and 41.7% (n = 10) during CAPD. As a group, the absolute AHI values increased from 3.4 ± 1.3 during NPD to 14.0 ± 3.5 during CAPD (P < 0.001 for comparison before and after transfer to CAPD). The individual changes in AHI values during the two different modes of PD are shown in Figure 3. The overall sleep pattern during NPD or CAPD is summarized in Table 4. Although there was no significant difference in the total sleep time during NPD or CAPD, the duration of sleep with hypoxia (oxygen saturation <95%) was substantially longer during CAPD (P = 0.03). In addition, there were significantly more frequent arousals after conversion to CAPD. The prevalence of sleep apnea during each mode of PD was significantly lower than the corresponding comparative group in part 1 of the study (P < 0.001 for NPD, P < 0.001 for CAPD).

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Figure 3.

AHI in 24 patients during NPD and after conversion to CAPD. *Four patients who developed de novo Cheyne-Stokes breathing (CSB) during CAPD but not during NPD; ^#patient who had CSB during NPD and CAPD. Horizontal bars represent mean ± SE values during each mode of PD. ^†P < 0.001 compared with values while on NPD.

To dissect the mechanisms that are responsible for the increased prevalence and severity of sleep apnea during CAPD compared with NPD, we measured fluid balance and respiratory mechanics with each therapeutic modality. Fluid balance was measured using multifrequency BIA analyses in 15 patients. As shown in Figure 4, the TBW content was significantly lower during stable NPD than CAPD, and the difference amounted to 6.6 ± 2.52% (32.8 ± 7.37 versus 35.1 ± 7.35 L; P = 0.004). This also was reflected by a significant difference in body weight between the two modalities (Table 5). Likewise, there were significant differences in ECW and ICW contents. To explore further the impact of NPD versus CAPD on fluid status during sleep, we performed BIA measurements just before and after NPD or the night dwell of CAPD to calculate the change in body fluid composition as a result of either NPD or CAPD during sleep. NPD achieved significantly larger volume of fluid removal as reflected by greater reductions in absolute body water contents and in hydration fraction expressed as percentage TBW of body weight (Table 5).

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Figure 4.

Fluid balance estimates in 15 patients during stable NPD (□) and CAPD (▪). All measurements were performed using multifrequency bioelectrical impedance analysis in the fasting state after drainage of peritoneal dialysate. Error bars are SD. TBW, total body water; ECW, extracellular water; ICW, intracellular water.

Pulmonary function tests using standard spirometry were obtained from these 15 patients just before and after NPD or the night dwell of CAPD. There was no difference in any of the spirometric parameters measured during NPD or CAPD (Table 6). In addition, there were no significant changes in pulmonary mechanics before and after NPD or the night dwell of CAPD (data not shown).

A total of seven patients were detected to have CSB. Two had CSB during NPD but not CAPD. One patient had CSB during both NPD and CAPD. Another four patients developed CSB during CAPD but not when they were undergoing NPD (Figure 5). These four patients all had sharp rises in AHI upon converting to CAPD, and they also had the high-end AHI values in this cohort. Three of them had no evidence of sleep apnea with AHI <5 during NPD, whereas the remaining patient already demonstrated significant sleep apnea (AHI = 29.7) during NPD that intensified (AHI rising to 59.2) upon conversion to CAPD. Echocardiography in these patients showed normal left ventricular ejection fraction and diastolic function. They did not have a history of cerebrovascular disorders.

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Figure 5.

Representative polysomnographic tracings in one patient with CSB. Shown here is a tracing spanning 300 s. Note the pattern of periodic crescendo and decrescendo breathing (arrow), drop in oxygen saturation after periodic apnea, and subsequent restoration of normal oxygen saturation after periodic breathing (*).